1. Field of the Invention
This invention relates to new 10-substituted camptothecin derivatives possessing anti-tumor activity (including carcinostatic activity) and to processes for the preparation of such derivatives. More particularly, this invention relates to new 5-R.sup.1 -7-R.sup.2 -camptothecin derivatives carrying a substituent R.sup.3 in the 10-position thereof and possessing anti-tumor activity with a low level of toxicity as well as processes for the preparation of 10-substituted camptothecin derivatives.
2. Description of the Prior Art
Camptothecin is a cytotoxic alkaloid isolated from leaves and barks of Camptotheca accuminata (Nyssaceae), a plant native to China, which has a pentacyclic structure consisting of a characteristic fused 5-ring system of quinoline (rings A and B), pyrroline (ring C), .alpha.-pyridone (ring D) and a six-membered lactone (ring E) and is distinguished by displaying a strong inhibitory activity toward biosynthesis of nucleic acid. In addition, camptothecin is a unique anti-tumor substance characterized by its rapid and reversible action and its lack of any cross-tolerance with the existing anti-tumor agents and by exhibiting a strong anti-tumor activity against experimentally transplanted carcinoma such as leukemia L-1210 in mice or Walker 256 tumor in rats. Although camptothecin is still regarded as one of the most potent substances possessing anti-tumor activity, the use of this compound itself for clinical treatments is significantly limited because of high toxicity.
Accordingly, a number of attempts have been made to reduce the toxicity of camptothecin while maintaining its anti-tumor activity by converting camptothecin chemically into its derivatives. The chemical modifications so far reported mainly concern the rings D and/or E of camptothecin, but the results of such modifications revealed only failure in maintaining expected anti-tumor activity and poor improvement in toxicity [J. Med. Chem., 19 (1976), 675]. From the chemotherapeutic point of view, therefore, it is of importance that the chemical modifications of camptothecin should be restricted in the rings A, B and C without effecting any change in the rings D and E which are conceivable to be one of the essential structural elements for the expression of the above mentioned characteristic biological activities.
Except for a method for functionalizing the 12-position of camptothecin reported in 1976 which comprises a series of troublesome conversion and purification operations starting with nitration at the 12-position [P. Pei-chuang et al., Hau Hsueh Hsueh Pao 33 (1975) 71; Chem. Abstr. 84 (1976) 115629p], however, no success was reported until 1979 in connection with chemical functionalization of camptothecin in a moiety involving the rings A, B and C. This is probably ascribable to the reasons that camptothecin itself is only sparingly soluble in various organic solvents and that camptothecin possessing the nature of heterocyclic rings in its molecule is resistant to the so-called electrophilic reactions conventionally carried out on aromatic rings. In the present status, such obstacles strongly discourage chemical modifications of camptothecin contemplated intellectually of preparing new classes for derivatives thereof.
Under the above mentioned circumstances, the present inventors previously found together with co-workers processes for preparing 5- and 7-substituted camptothecins (U.S. Pat. No. 4,399,282) by introducing (1) hydroxymethyl group into 7-position of camptothecin by subjecting camptothecin to a radical reaction with methanol by the aid of sulfuric acid and a peroxide (such as potassium persulfate, sodium persulfate, ammonium persulfate, hydrogen peroxide or a tertiary-butyl peroxide) wherein the reaction is carried out usually by dissolving camptothecin in an aqueous solution of methanol-sulfuric acid, adding thereto a peroxide as a radical reaction initiator (Japanese Laid-open Patent Appln. No. 56-12391), (2) hydroxy group into 5-position of camptothecin by treating camptothecin with sulfuric acid, water and a persulfate (such as sodium persulfate, potassium persulfate and ammonium persulfate) in the presence of a metal ion (such as silver salts such as silver nitrate, silver sulfate, silver carbonate or silver acetate or a ferrous salt such as ferrous sulfate, ferrous chloride and ferrous oxide) under heat and agitation (Japanese Laid-open Patent Appln. No. 56-12392), and (3) an alkyl or aralkyl group into 7-position of camptothecin efficiently in a single step by subjecting camptothecin to a radical reaction with a compound of the general formula: RX (wherein R stands for an alkyl group or an aralkyl group, and X for --CH.sub.2 OH, --COOH, --CHO, --CO--R or ##STR2## preferably in a large excess amount by the aid of sulfuric acid, water and a peroxide (such as hydrogen peroxide or tert-butylhydroperoxide) in the presence of a metal ion (such as ferrous sulfate, ferrous chloride or ferrous oxide) usually under ice-cooling and agitation and thereafter stirring while warming the mixture to room temperature (Japanese Laid-open Patent Appln. No. 56-158786). Further, the present inventors prepared together with co-workers a great number of new camptothecin derivatives possessing anti-tumor activity with slight toxicity from these 5- and 7-substituted camptothecin derivatives (U.S. Pat. Nos. 4,399,276 and 4,399,282) according to the process wherein 7-hydroxymethylcamptothecin is acylated with an acylating agent usually capable of acylating hydroxy group, for example, a halide of a carboxylic acid (such as formic acid, acetic acid, propionic acid, butyric acid, phenylacetic acid, succinic acid, trifluoroacetic acid or the like aliphatic carboxylic acid or benzoic acid or the like aromatic carboxylic acid) or a carboxylic acid anhydride whereby the hydroxy group or groups of the camptothecin is acylated to obtain 7-acyloxymethylcamptothecins or 20-O-acyl-7-acyloxymethylcamptothecins or wherein 7-hydroxymethylcamptothecin is oxidized with an oxidizing agent usually capable of oxidizing hydroxymethyl group to carboxy group, for example, an anhydrous chromate, a bichromate or a permanganate whereby 7-carboxycamptothecin is obtained, which is then esterified according to a usual manner with an alcohol (such as methanol, ethanol, propanol or butanol) to obtain 7-alkoxycarbonylcamptothecins (Japanese Laid-open Patent Appln. No. 56-12393), the process wherein 5-alkoxycamptothecins are obtained by dissolving 5-hydroxycamptothecin in a lower alcohol (such as methanol, ethanol, propanol or butanol), adding thereto an acid (such as hydrochloric acid, sulfuric acid or boron fluoride etherate) as catalyst, and heating the mixture, or wherein 5-acyloxycamptothecins or 20-O-acyl-5-acyloxycamptothecins are obtained by acylating 5-hydroxycamptothecin with a reactive acid derivative such as a halide of a carboxylic acid (such as formic acid, acetic acid, propionic acid, butyric acid, phenylacetic acid, succinic acid or trifluoroacetic acid or benzoic acid) or an acid anhydride (Japanese Laid-open Patent Appln. No. 56-12394), the process wherein camptothecin-7-aldehyde is obtained directly from the 7-hydroxymethylcamptothecin by treating the 7-hydroxymethylcamptothecin with various cationoid reagents without using any oxidizing agent [The cationoid reagent includes a variety of mineral acids (such as sulfuric acid, hydrochloric acid, perchloric acid, hydrobromic acid and the like), organic acids (such as acetic acid, propionic acid, benzoic acid, monochloroacetic acid, trifluoroacetic acid, p-toluenesulfonic acid and methanesulfonic acid), Lewis acids (such as boron trifluoride-ether, aluminum chloride and stannic chloride), organic acid halides (such as p-toluenesulfonyl chloride, phenylacetyl chloride and the like) and chlorinating agents (such as phosphorus oxychloride, thionyl chloride and the like inorganic acid chlorides) and is preferably used in a solvent such as water, dimethylformamide or dioxane at a temperature of 90.degree.-100.degree. C. or under reflux] (Japanese Laid-open Patent Appln. No. 57-116075), and the process wherein 7-alkoxymethylcamptothecins and 7-dialkoxymethylcamptothecins are obtained by treating 7-hydroxymethylcamptothecin in a lower alcohol (such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, n-amyl alcohol, isoamyl alcohol or t-amyl alcohol) or an aralkyl alcohol (such as benzyl alcohol, phenethyl alcohol or phenylpropanol) with an acid (such as sulfuric acid, hydrochloric acid, hydrobromic acid, perchloric acid; Lewis acids, for example, boron trifluoride aluminum chloride and stannic chloride; trifluoroacetic acid, trichloroacetic acid, benzenesulfonic acid, toluenesulfonic acid or methanesulfonic acid) at a temperature from room temperature to the boiling reflux temperature from room temperature to the boiling reflux temperature under such condition that the use of the acid in a catalytic amount or several molar equivalent amount affords a 7-dialkoxymethylcamptothecin exclusively or preferentially, but the use of the acid in a large excess amount, e.g. in a 150-250 molar equivalent amount affords a 7-alkoxymethylcamptothecin exclusively or preferentially (In the event that both of a 7-dialkoxymethylcamptothecin and a 7-alkoxymethylcamptothecin are formed concurrently, both products can be separated and purified by subjecting them to column chromatography on silica gel or high speed fluid chromatography) (Japanese Laid-open Patent Appln. No. 57-116076). However, the sorts of camptothecin derivatives prepared according to these processes are still limitative.
Noteworthy in recent years is that 10-hydroxycamptothecin isolated from Camptotheca acuminata was reported to be lower in toxicity than camptothecin itself but higher in anti-tumor activity (a certain medical magazine in China, 1978). For further extensive researches on the relation between substituents in camptothecin derivatives and anti-tumor activity and/or toxicity, therefore, there is still a great demand in this art for developing further new classes of camptothecin derivatives possessing a low level of toxicity while maintaining the inherent anti-tumor activity by chemical modifications of camptothecin itself or derivatives thereof in a simple manner.